Decline In Prostate-specific Antigen Levels Research Articles

Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ, UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.J Clin Oncol 2004;22:1025–33

Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of ≥50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. AiPCa patients were randomized to undergo AAWD alone (n = 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n = 128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P = .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P = .02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.

Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer

Objectives To determine whether supplemental amounts of soy isoflavone (genistein-rich extract) would lower prostate-specific antigen (PSA) levels more than 50% in patients with prostate cancer (CaP). Methods A total of 62 men (mean age 73.6 years, range 61.4 to 89.3) with histologically proven CaP who had two consecutive elevated PSA readings were accrued during a 13-month period. An open-label pilot study was conducted for 6 months in which the patients took capsules containing the genistein-rich extract three times daily by mouth. The subjects were in one of five groups: after radical retropubic prostatectomy (n = 9), after radiotherapy (n = 17), after both radical retropubic prostatectomy and radiotherapy (n = 6), off-cycle during hormonal therapy (intermittent hormones; n = 14), or active surveillance (n = 16). The primary endpoint for the trial was a 50% reduction in the PSA level at 6 months compared with before treatment. Results Of the 62 men enrolled, 52 were available for evaluation at 6 months. Three patients discontinued because of adverse events (diarrhea) and seven because of personal choice. One of 52 patients had a more than 50% reduction in the PSA level (1.9% response, 95% confidence interval 0.1% to 10.3%). An additional 7 patients had PSA reductions that were less than 50%. All 8 patients with lower PSA levels at 6 months were in the active surveillance (watchful waiting) treatment subgroup. Repeated measure regression models allowing for correlation between initial levels and change also indicated a decline in PSA in this group compared with other groups: 0 of 52 had a complete response, 9 (17%) had a partial response, 8 (15%) had stable disease, and 35 (67%) had disease progression. In the 9 patients with a partial response, 6 had pathologic findings that were moderately differentiated, 2 had well-differentiated findings, and 1 had poorly differentiated findings. Therefore, the response in this group of patients did not appear to be driven by the Gleason score. The total testosterone level was lowered in one of the patients responding, but it was higher in five others. Conclusions A genistein-rich extract as the sole treatment for CaP did not reduce PSA levels by 50% or more in 51 of 52 subjects. Thus, it does not appear to be an effective treatment for CaP when given alone. However, 8 of 13 evaluated patients in the active surveillance group had either no rise or a decline in PSA levels of less than 50%. More study is warranted for those choosing active surveillance.

Phase II trial of cyclophosphamide, vincristine, and dexamethasone in the treatment of androgen-independent prostate carcinoma. Daliani DD, Assikis V, Tu SM, Papandreou CN, Pagliaro LC, Holtkamp T, Wang X, Thall PF, Logothetis CJ, Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX: Cancer 2003;97:561–567

Background In this Phase II study, the authors assessed the toxicity and antitumor activity of a combination of oral cyclophosphamide, oral low-dose dexamethasone, and intravenous vincristine (CVD) in patients with metastatic androgen-independent prostate carcinoma (AI-PCa). Methods Patients with histologic proof of adenocarcinoma of the prostate progressing despite adequate hormonal therapy and adequate organ function were treated with oral cyclophosphamide, 250 mg/daily (Days 1–14); intravenous vincristine, 1 mg daily (Days 1, 8, 15); and oral dexamethasone, 0.75 mg twice a day (Days 1–14) in 28-day cycles. Study endpoints were toxicity, rate of prostate specific antigen (PSA) decline > 50%, and/or measurable disease response. Results Fifty-two (95%) of 55 registered patients were evaluable. The majority (65%) of patients had received prior chemotherapy. The median number of treatment cycles given was 2 (range, 1–7 cycles). Twenty-nine percent of the patients were found to have a >50% decline in PSA level compared with baseline levels, and 25% of the patients with bidimensionally measurable soft-tissue or visceral disease were found to have a partial response. The median progression-free survival duration was 10 weeks, and the median overall survival duration was 10.6 months. There were no thromboembolic events, and hematologic and nonhematologic toxicity was minimal. Conclusions CVD was found to be an active and well-tolerated regimen for AI-PCa. The low toxicity profile makes CVD a useful treatment option for patients with significant comorbidities and high risk for treatment-related toxicity, especially thromboembolic events and myelotoxicity. Copyright 2003 American Cancer Society.

Prostate-Specific Antigen Levels and Prognosis in Patients with Hormone-Refractory Prostate Cancer Treated with Low-Dose Dexamethasone

Objective: The efficacy of low-dose dexamethasone (DXM) therapy in patients with hormone-refractory prostate cancer (HRPC) was evaluated. Patients and Methods: Prostate-specific antigen (PSA) response and survival following DXM therapy were analyzed in 27 Japanese patients exhibiting HRPC. Concurrent therapies and antiandrogen withdrawal syndrome, which may affect PSA levels and palliative effects, were excluded from the study. A dose of 1.5 mg of DXM was administered, and androgen deprivation therapy was maintained during DXM therapy. A decline in PSA levels of at least 50% from baseline was considered a significant PSA response. Prognostic factors for PSA response and survival were examined by univariate and multivariate analyses. Results: A significant PSA response was observed in 16 of the 27 cases (59.3%). Median survival period of patients exhibiting significant PSA response was 15.9 months and was significantly longer than that of patients demonstrating a decline in PSA of less than 50% (median 7.7 months, p < 0.0001). Effect on pain control also correlated with the significant PSA response. No meaningful prognostic factors for PSA response were detected; however, a PSA decline of greater than 50% was the prognostic factor for survival. Conclusion: DXM therapy remains one of the most beneficial treatment modalities in patients with HRPC.

Treatment of Metastatic Hormone Refractory Prostate Cancer with Ketoconazole, Hydrocortisone, and Cyclophosphamide

ABSTRACTObjective: Patients with metastatic hormone‐refractory prostate cancer have a poor overall survival rate. Newer agents have shown promise in slowing disease progression but are mostly ineffective in improving the overall survival rate, are toxic, and require intravenous administration. In an attempt to maintain treatment efficacy, but to minimize toxicity and improve ease of use, we conducted a pilot trial of an oral regimen consisting of ketoconazole, hydrocortisone, and cyclophosphamide combination therapy.Materials and Methods: Twenty‐seven patients with metastatic hormone‐refractory prostate cancer were treated with an oral regimen of ketoconazole, 400 mg tid, and hydrocortisone, 20 mg qam and 10 mg qpm, on Days 1–28. Cyclophosphamide, 100 mg/m2, was added on Days 1–14. Treatment was recycled every 28 days. Progression of disease was defined by a progressively rising prostate specific antigen (PSA) level, new lesions as seen on bone scans, or progression of soft‐tissue disease. Patient age ranged from 57 to 87 years. Performance status (PS; Eastern Cooperative Oncology Group scale) was 0–2. Pretreatment PSA values ranged from 5.8 ng/mL to 3400 ng/mL (median 68).Results: Twenty‐one (78%) of 27 patients with elevated PSA levels demonstrated a ≥50% decline in PSA level for 3 consecutive months. Of the remaining six patients (22%), two progressed within 3 months, two withdrew from the study due to toxicity, and two responded with &lt;50% decline in PSA level. Nadir PSA values ranged from &lt;0.2 to 155, with a median nadir of 5.1. Mean and median declines in PSA levels were 79% and 93%, respectively. The duration of response ranged from 3 to &gt;96 months, with a median response duration of 9 months. Twenty‐two (81%) of 27 patients experienced no significant toxicity, 4 of 27 patients experienced Grade I–III gastrointestinal toxicity, and 1 of 27 patients experienced Grade III hematologic toxicity.Conclusions: The combination of ketoconazole, hydrocortisone, and cyclophosphamide is a well‐tolerated oral regimen for the treatment of patients with metastatic hormone‐refractory prostate cancer with significant disease activity, and it warrants further investigation.

Recent advances in chemotherapy for advanced prostate cancer.

Recently, several important studies have validated prostate-specific antigen (PSA) as a reliable measure of response to chemotherapeutic treatment in advanced hormone-refractory prostate cancer. Furthermore, although chemotherapy in this setting has always been considered palliative, several analyses of recent clinical trials have demonstrated a significant association between declines in PSA values of 50% or more and prolonged survival. Mitoxantrone, in combination with prednisone, has been shown to provide significant palliation and improved quality of life. The use of combinations of chemotheraputic agents also seems to provide significantly superior objective and subjective responses compared with single-agent regimens. In particular, estramustine has been shown to synergize many of the agents used in prostate cancer treatment and has been demonstrated to provide significant palliation and decline in PSA levels in combination with vinblastine, vinorelbine, etoposide, paclitaxel, and docetaxel. The results of several important trials of the taxanes both as single agents and in combination with estramustine have been completed in the past year and have demonstrated that these agents are very effective in the treatment of hormone-refractory prostate cancer.

Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group.

Prostate-specific antigen (PSA) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells. For patients with metastatic disease, changes in PSA will often antedate changes in bone scan. Furthermore, many but not all investigators have observed an association between a decline in PSA levels of 50% or greater and survival. Since the majority of phase II clinical trials for patients with androgen-independent prostate cancer (AIPC) have used PSA as a marker, we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting. We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters. We defined four patient groups: (1) progressive measurable disease, (2) progressive bone metastasis, (3) stable metastases and a rising PSA, and (4) rising PSA and no other evidence of metastatic disease. The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials. We propose that investigators report at a minimum a PSA decline of at least 50% and this must be confirmed by a second PSA value 4 or more weeks later. Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period. Some investigators may want to report additional measures of PSA changes (ie, 75% decline, 90% decline). Response duration and the time to PSA progression may also be important clinical end point. Through this consensus conference, we believe we have developed practical guidelines for using PSA as a measurement of outcome. Furthermore, the use of common standards is important as we determine which agents should progress to randomized trials which will use survival as an end point.

Prostatic involvement in men with febrile urinary tract infection as measured by serum prostate-specific antigen and transrectal ultrasonography.

To determine the frequency of prostatic involvement in men with community-acquired febrile urinary tract infection. This prospective study included 70 men (18-85 years old) who had a fever of >/=38.0 degrees C, symptoms or signs of urinary tract infection and a positive urine culture. Serum prostate-specific antigen (PSA) was measured and transrectal ultrasonography of the prostate and seminal vesicles performed during the acute phase of the disease and during a 1-year follow-up. Although only six patients had a tender prostate on digital rectal examination, the initial serum PSA level was elevated in 58 (83%) patients (median 14 ng/mL, range 0.54-140). There was no correlation between PSA levels, patient age, inflammatory response to infection or presence of positive blood cultures. Despite a rapid decline in PSA level after one month, there was a protracted decrease in some patients. After 3 months the median prostate volume was reduced by 31% (range 11-54; P<0.001) in 46 of 55 patients examined, and the width of the right and left seminal vesicle was reduced by 14% and 22%, respectively. The reductions in PSA and prostate volume were significantly correlated (r=0.36, 95% confidence interval 0.09-0.58; P=0.01). These results show that the prostate and seminal vesicles are frequently involved in men with febrile urinary tract infection and that PSA may be a useful marker of prostatic infection. The slow decline of PSA levels in some patients after appropriate antibiotic treatment indicates a protracted healing process and should be considered when PSA is used to detect prostate cancer.

Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer.

With an hypothesis that post-chemotherapy changes in serum prostate-specific antigen (PSA) levels might serve as a surrogate marker for assessing prostate cancer outcome (i.e., survival), we studied the relationship between pretherapy and post-therapy prognostic factors and survival in patients with androgen-independent prostate cancer. A prognostic model for survival based on pretherapy and post-therapy parameters was developed from the clinical data on 254 patients with androgen-independent prostate cancer treated with 11 different protocol therapies at Memorial Sloan-Kettering Cancer Center. The model was validated by use of an independent dataset of 541 patients enrolled in two randomized phase III trials. In multivariate analysis, a post-therapy decline in PSA levels of 50% achieved in 12 weeks was a statistically significant factor associated with survival (two-sided P = .0012). A similar outcome was obtained with the use of an 8-week time frame. Elevated pretherapy level of serum lactate dehydrogenase (two-sided P = .0001), lower pretherapy level of hemoglobin (P = .0001), and younger age (two-sided P = .0430) had a statistically significant negative impact on outcome. Median survival times were 23, 17, and 9 months for low-, intermediate-, and high-risk groups of patients defined by the prognostic model, respectively. This study confirms the prognostic value of a post-therapy decline in PSA of 50% or greater from baseline in relation to survival in patients with androgen-independent prostate cancer treated with a variety of therapies. Two consecutive determinations at 4-week intervals can be used as an end point for efficacy in phase II trials of therapies in this disease.

Incidence and Characteristics of Antiandrogen Withdrawal Syndrome in Prostate Cancer after Treatment with Chlormadinone Acetate

Objectives: In patients with progressive prostate cancer who have been treated with surgical or medical castration plus an antiandrogen, antiandrogen withdrawal can result in a significant decline in serum prostate-specific antigen (PSA). Although the incidence of antiandrogen withdrawal syndrome after combination treatment with the nonsteroidal antiandrogen flutamide has been thoroughly documented, the phenomenon clearly occurs in many other combination therapies and is presently being widely investigated. This paper would like to contribute to this effort by describing the endocrine withdrawal phenomenon in patients treated with combinations of castration plus chlormadinone acetate, ethynylestradiol or estramustine phosphate. Materials and Methods: Clinical records of 68 prostate cancer patients who had been treated with surgical castration plus the administration of chlormadinone acetate, ethynylestradiol or estramustine phosphate, and who had shown clinical progression associated with a steady increase in serum PSA, were investigated. Forty-one cases were evaluable for changes in PSA after discontinuation of the hormonal agents. Results: Of 28 patients who had been treated with chlormadinone acetate, 12 (42.9%) revealed 50% or more decline in PSA level following withdrawal of the agent. Among these, 5 cases (17.9%) showed subjective and/or objective improvements. There was no significant difference in histological grade of the tumor at diagnosis, mode of progression, time interval from the start of endocrine therapy to discontinuation of the hormonal agents, or PSA levels at withdrawal of the agents between patients who did develop antiandrogen withdrawal syndrome and those who did not. Conclusion: When a steady increase in serum PSA is noted in a prostate cancer patient who has been treated with castration plus a steroidal antiandrogen, discontinuation of the antiandrogen may benefit the patient.

A pilot study of intermittent androgen deprivation in advanced prostate cancer.

To assess the feasibility of intermittent hormone therapy for metastatic prostate cancer. Sixteen patients with metastatic carcinoma of the prostate were treated using a protocol of intermittent hormone therapy with the luteinizing hormone-releasing hormone (LHRH) analogue leuprorelin at a dose of 3.75 mg every 4 weeks. The protocol required that hormone therapy be stopped when the response was stable, and was designed to assess the duration of the unmaintained response and the probability of a second response to re-initiation of leuprorelin. Eleven of the 16 patients had a stable hormone response and stopped therapy 3-9 months (mean 5.5) from the start of treatment. The mean (range) duration of the unmaintained response, as judged by monitoring symptoms and serum prostate specific antigen (PSA) levels every month was 4 (2-8) months in the seven patients who had bone metastases and was 3, 3 and 6 months in the three with only loco-regional disease (one patient temporarily discontinued follow-up). As the immediate re-induction of hormone therapy was not mandatory in asymptomatic patients at the time of progression, the mean (range) period off hormone therapy was 8 (3-13) months in those eight patients with bone metastases and was 3, 36 and 42 + months in the three presenting with loco-regional disease. All 10 patients who re-initiated hormone therapy had a second hormone response, in six of which led to a decline in PSA level to < 2 ng/mL. During the period off hormone therapy no patient developed irreversible symptoms. The temporary cessation of hormone therapy early during the response in patients with metastatic carcinoma of prostate is associated with biochemical evidence of relatively early progression in most cases, but can be associated with significant periods off therapy and with a high chance of a second hormone response. The value of this approach to the quality and duration of patients' lives requires a prospective comparative evaluation.

PSA levels and the rate of positive surgical margins in radical prostatectomy specimens preceded by androgen blockade in clinical B 2 (T2bNxMo) prostate cancer

Objectives Neoadjuvant hormonal therapy reduces positive margins in patients undergoing radical prostatectomy. All patients experience a decrease in serum prostate specific antigen (PSA), but not always to a level that is nondetectable. The results of several prospective, randomized trials indicate that the incidence of positive margins decreases with the use of androgen deprivation prior to radical prostatectomy. It has been suggested that a greater decline in PSA levels would result in fewer positive margins. In a recent US trial of patients with T2bNxMO prostate cancer, we reported that 18% of patients randomized to receive 3 months of leuprolide acetate and flutamide had positive margins, compared to 48% of those who had radical prostatectomy alone ( P <0.001). We correlated the PSA levels prior to and following androgen deprivation and the presence of a positive margin following radical prostatectomy (RP). Methods One hundred and thirty-seven of 149 patients randomized to receive presurgery androgen deprivation (AD) underwent radical prostatectomy. Of these, 135 had a PSA level obtained both prior to androgen deprivation and prior to surgery. We analyzed the percent positive margins in patients whose PSA values became undetectable and in those whose values remained above 0.1 ng/mL despite androgen deprivation. Results Eight of 43 patients (19%) with a nadir PSA ≤0.1 ng/mL had a positive surgical margin and 16/92 (17%) with a nadir PSA >0.1 ng/mL had tumor at the margin. There were no statistical differences in these two groups ( P = 1.0 by Fisher's Exact Test [two-tailed], and the Pearson correlation was −0.015). Conclusions There was no correlation between an undetectable PSA and a PSA >0.1 ng/mL and the presence of tumor at the margin when 3 months of AD was given prior to RP. It is possible that longer periods of AD prior to RP will reduce PSA to an undetectable level in a higher percent of patients. However, these data suggest that an undetectable level will not result in less positive margins.

Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II multicenter trial

Objectives. The safety, efficacy, and pharmacokinetics of the nonsteroidal antiandrogen bicalutamide were investigated in a Phase II trial in 150 patients with metastatic prostate cancer. Methods. Patients took bicalutamide, 50 mg daily, in an open-label multicenter North American trial. Results. The objective response rate (modified European Organization on Research and Treatment of Cancer [EORTC] criteria) was 70% (57% partial, 13% stable); 59 (39%) of 150 patients had either a >90% decrease in prostate-specific antigen (PSA) levels or a decline to <4 ng/mL. Extent of disease on the bone scan was a significant predictor of response. Patients with <6 metastatic lesions were more likely to respond. Breast pain and gynecomastia occurred in 76% and 60% of patients, respectively. Gastrointestinal toxicity was very infrequent (diarrhea, 5%) The mean drug plasma concentration was 8528 (±2928) ng/mL. Conclusions. Bicalutamide, 50 mg daily, was well tolerated and has efficacy in metastatic prostate cancer. The percentage of men who had >90% decline in PSA levels is less than observed with surgical or medical castration and has led to trials using this antiandrogen at higher doses as monotherapy.

Antiandrogen withdrawal syndrome in prostate cancer after treatment with steroidal antiandrogen chlormadinone acetate

Objectives A case report is presented of 2 patients whose levels of serum prostate-specific antigen (PSA) improved after the withdrawal of a steroidal antiandrogen. Methods Two cases with prostate cancer had been treated with surgical castration and the steroidal antiandrogen chlormadinone acetate (CMA), and, on disease progression, the administration of CMA was terminated. Results Following withdrawal of CMA, a fall in PSA levels and remarkable clinical improvement were observed in both cases. One patient revealed a decrease and the other an increase in serum prostate acid phosphatase after the discontinuation of CMA. Serum levels of testosterone, prolactin, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione were not significantly elevated after CMA withdrawal. Conclusions Withdrawal of the steroidal antiandrogen CMA resulted in a decline in PSA levels and clinical improvement in prostate cancer patients with disease progression. Changes in testosterone, prolactin, or adrenal androgens were not a cause of the antiandrogen withdrawal syndrome.